Clinical studies have shown a correlation between Parkinson's disease (PD) and Type 2 Diabetes (T2D). We propose a preclinical investigation of relationship between these diseases. The long term objective of this project is twofold: to determine how these diseases are linked mechanistically and to investigate possible therapeutic interventions. Our first aim is to investigate PD as a risk factor for T2D. We will inject 6-hydroxydopamine into the nigrostriatal pathway and analyze the effect of dopamine depletion on insulin signaling in the brain and periphery. In our second experimental aim, we will use a model of insulin resistance (high fat diet) to analyze mechanisms by which diabetes mellitus may play a role in development of PD. High blood glucose and insulin levels have been shown to affect dopamine function in the brain. We will analyze the effects of insulin resistance and hyperinsulinemia on brain insulin signaling, DA function in the basal ganglia, and neural oxidative stress levels. Our final aim will investigate whether insulin resistance exacerbates dopaminergic degeneration in a partial lesion model, and whether a pharmacological intervention can alleviate this effect. This is important because environmental factors that cause oxidative damage, such as pesticides, have been shown to increase the likelihood of developing PD. It is important to determine whether the effects of environmental exposure to oxidants could be compounded by insulin resistance. Determining how these diseases are linked is the first step in disrupting this relationship and decreasing the likelihood that an individual who suffers from either PD or T2D will later develop both diseases. In addition, we will also provide greater mechanistic insight into the pathologies mediating each specific disease. Relevance to public health: Many Parkinson's patients have abnormal glucose tolerance, which may be exacerbated by L-DOPA therapy and increase side effects of therapy such as dyskenesias. In addition, a recent clinical study has found individuals with T2D to be 83% more likely to develop PD than their non-diabetic counterparts, indicating T2D as a possible risk factor for PD. A mechanistic association between T2D and PD demands attention. Failure to address this looming clinical issue could result in increased incidence of each disease, increased disease severity, and decreased therapeutic effectiveness.